memory in subjects with mini-mental state examination of 24-26

ABSTRACT

The invention thus pertains to the use of a composition comprising: (a) uridine or uridine phosphate; and (b) docosahexaenoic acid and/or eicosapentaenoic acid, for improving memory and/or the treatment or prevention of impaired memory function, in a subject with a mini-mental state examination of 24-26, wherein said composition is enterally administered to the subject. In the MMSE test, any score of 27 or higher (out of 30) is effectively normal. In the patients with dementia, 20-26 indicates mild dementia, 10-19 moderate dementia, and below 10 severe dementia. It was the present inventors&#39; belief that within the group of 20-26, the memory impairment in the sub-group of 24-26 may even be reversible, as the pathological pathways have just started to develop. In this group of subjects the pathological pathways have just started to develop. Clinical studies show excellent results for this subgroup.

FIELD OF THE INVENTION

The invention relates to the use of a composition for improving memoryfunction, in a subject with a mini-mental state examination of 24-26.

BACKGROUND OF THE INVENTION

Memory impairment is a serious shortcoming in many humans, particularlythose suffering from Alzheimer's disease and/or elderly. Suchimpairments often have serious consequences, such as reduced quality oflife, difficulties in performing the activities of daily living,potentially resulting in hospitalization or institutionalization.

Several treatments have been suggested for the improvement of memoryfunction in subjects. However, very few have been proven effective.Moreover, the administration of several nutritional ingredients has alsobeen suggested.

SUMMARY OF THE INVENTION

Nutritional therapy is particularly desired in subjects who haverelatively mild symptoms of memory impairment, i.e. subjects with amini-mental state examination score (MMSE) of 24 to 26. The presentinventors have recognized that in this particular subgroup memoryimprovement has enormous effect for the subject activities of dailyliving and quality of life. This subgroup of subjects is distinct inthat the pathological pathways have just started to develop. In the MMSEtest, any score of 27 or higher (out of 30) is effectively normal. Inthe patients with dementia, 20-26 indicates mild dementia, 10-19moderate dementia, and below 10 severe dementia. It was the presentinventors' belief that within the group of 20-26, the memory impairmentin the sub-group of 24-26 may even be reversible, as the pathologicalpathways have just started to develop. It would be highly desired toimprove the memory function of this subgroup of subjects, as this maydelay the need or reduce the dosage of treatment with pharmaceuticaldrugs. Moreover, improvements in subjects with a MMSE of 24 to 26 canpostpone the need for a subject to be hospitalized or institutionalized,enable a longer independent living, improve the quality of life orimprove the ability to perform daily activities.

The subgroup of subjects with a MMSE score of 24 to 26 comprises twopopulations. Firstly, it comprises those subjects who do not receivemedication for memory impairment, i.e. the drug naïve subjects. Thetreatment of this subgroup is particularly preferred as in thesesubjects the balance between side effects and benefits of pharmaceuticalintervention is still negative. Providing nutritional therapy to thesesubjects is desired because of the relative lack of negative sideeffects. For subjects with a MMSE of 24 to 26 who are drug naïve, it isparticularly important to develop a therapy which delays the point intime where pharmaceutical drugs have to be administered.

Secondly, the subgroup of subjects with a MMSE score of 24 to 26comprises a population of subjects with a very mild form of Alzheimer'sDisease. Memory improvement through nutritional therapy is particularlydesired in subjects with a very mild form of Alzheimer's Disease. Ifimprovement of memory function could be achieved pharmaceuticalintervention could be reduced or even postponed if significantimprovements are observed.

It is however particularly difficult to find a (nutritional) compositionwhich effectively improves memory function in the group with a MMSE of24 to 26 as the pathological pathways have only started to develop andsymptoms are very mild. Detecting differences between control andtreatment group is particularly difficult, and hence effective treatmentrequires intensive testing.

The present inventors surprisingly found, through clinical study, thatadministration of a composition containing (a) uridine or uridinephosphate; and (b) docosahexaenoic acid and/or eicosapentaenoic acidshowed a significant improvement of memory function in subjects with aMMSE of 24 to 26. Compliance and tolerability were very high and sideeffects were relatively low. It was particularly surprising that thepresent clinical data showed an actual improvement in memory function,more than just a reduction in the rate of decline in memory function.Additionally it was found that in this subgroup the delayed recallfunction was significantly improved. The results of the clinical studyare summarized in the examples.

DETAILED DESCRIPTION OF THE INVENTION

The invention thus pertains to the use of a composition comprising:

-   -   a. uridine or uridine phosphate; and    -   b. docosahexaenoic acid and/or eicosapentaenoic acid        for improving memory and/or the treatment or prevention of        impaired memory function, in a subject with a mini-mental state        examination of 24-26, wherein said composition is enterally        administered to the subject.

Subjects

The present invention relates to subjects with a mini-mental stateexamination of 24, 25 or 26, i.e. of 24-26. The mini-mental stateexamination (MMSE) is a brief 30-point questionnaire test that is usedto assess cognition. In the time span of about 10 minutes it samplesvarious functions including memory and orientation. The MMSE testincludes simple questions and problems in a number of areas: the timeand place of the test, repeating lists of words, language use andcomprehension, and basic motor skills. Any score of 27 or higher (out of30) is effectively normal; 20-26 indicates mild dementia; 10-19 moderatedementia, and below 10 severe dementia. The MMSE is a standardized test.Copyrights prevent the inventors from including a copy of thequestionnaire into the specification, but it is readily accessible onthe internet and available through copyright owner PsychologicalAssessment Resources (PAR). It is first introduced by Folstein et al.(Psych Res 12:189, 1975), and is widely used with small modifications toassess cognition.

The subjects as treated in the present invention have a mini-mentalstate examination score of 24-26 and are preferably drug naïve and/orsuffer from a very mild form of Alzheimer's disease, preferably drugnaïve subjects with a very mild Alzheimer's disease and a MMSE of 24-26.The term “drug naïve” as used in the present invention refers tosubjects who do not ingest one or more of cholinesterase inhibitors,N-methyl-D-aspartate (NMDA) antagonists and ginkgo biloba. In theclinical study presented here, it was found that the present compositionis effective in drug naïve subjects. The subject is preferably a human,preferably an elderly human, preferably at least 50 years of age.

Memory

The present invention relates to use of the present composition for (i)the improvement of memory and/or (ii) treatment and/or prevention ofimpaired memory function. Alternatively, the present invention providesa method for (i) the improvement of memory and/or (ii) treatment and/orprevention of impaired memory function in a subject in need thereof,said method comprising the administration of the present composition tosaid subject. Particularly, the present invention relates to thetreatment of an impaired memory function. It was found that the memoryfunction actually improved when the present composition was administeredto the subject. The memory function of a human subject can suitably bedetermined using the (modified) ADAS-cog, Wechsler Memory Scale, WMSrevised.

It was particularly found that in these subjects the delayed recallfunction was improved. Delayed recall function can be measured by aprose recall task 30-minute delay interval. Delayed recall of a prosepassage is not a measure to differentiate clearly between very milddementia of the Alzheimer type and normal ageing. Hence, the presentcomposition can also advantageously help subjects not (yet) sufferingfrom Alzheimer's disease in improving the delayed recall function.Hence, in a preferred embodiment the invention provides a method forimproving delayed recall and/or the treatment and/or prevention of animpaired delayed recall function.

Uridine

Preferably the present composition comprises uridine and/or uridinephosphate. Preferably the present composition comprises one or moreuridine phosphates selected from uridine monophosphate (UMP), uridinediphosphate (UDP) and uridine triphosphate (UTP).

Most preferably the present composition comprises UMP. Preferably atleast 50 wt. % of the uridine in the present composition is provided byUMP, more preferably at least 75 wt. %, most preferably at least 95 wt.%. The present method preferably comprises the administration of uridine(the cumulative amount of uridine, deoxyuridine, uridine phosphates,uracil and acylated uridine derivatives) in an amount of 0.08-3 g perday, preferably 0.1-2 g per day, more preferably 0.2-1 g per day. Thepresent method preferably comprises the administration of a compositioncomprising uridine in an amount of 0.08-3 g UMP per 100 ml liquidproduct, preferably 0.1-2 g UMP per 100 ml liquid product, morepreferably 0.2-1 g per 100 ml liquid product. Preferably 1-37.5 mg UMPper kilogram body weight is administered per day. The required dosagesof the equivalents on a weight base can be calculated from the dose forUMP by taking equimolar amounts using the molecular weight of theequivalent and of UMP, the latter being 324 Dalton.

Docosahexaenoic Acid and/or Eicosapentaenoic Acid

The present composition preferably comprises at least docosahexaenoicacid (22:6 ω-3; DHA) and/or eicosapentaenoic acid (20:5 ω-3; EPA),preferably DHA and EPA. The DHA and/or EPA is preferably provided astriglycerides, diglycerides, monoglycerides, free fatty acids or theirsalts or esters, phospholipids, lysophospholipids, glycerol ethers,lipoproteins, ceramides, glycolipids or combinations thereof.Preferably, the present composition comprises at least DHA intriglyceride form.

The present method preferably comprises the administration of 400-5000mg (DHA+EPA) per day, more preferably 500-3000 mg per day, mostpreferably 1000-2500 mg per day. The proportion of (DHA+EPA) of thetotal fatty acids present in the composition is preferably 5-50 wt. %,more preferably 10-45 wt. %, most preferably 15-40 wt. %. The presentmethod preferably comprises the administration of DHA, preferably in anamount of 300-4000 mg per day, more preferably 500-2500 mg per day.

The present composition preferably contains a very low amount ofarachidonic acid (AA). Preferably the weight ratio DHA/AA in the presentcomposition is at least 5, preferably at least 10, more preferably atleast 15, preferably up to e.g. 60 or up to 30. The present methodpreferably comprises the administration of a composition comprising lessthan 5 wt. % arachidonic acid based on total fatty acids, morepreferably below 2.5 wt. %, e.g. down to 0.5 wt %. The ratioomega-6/omega-3 fatty acids in the present product is preferably below0.5, more preferably below 0.2, e.g. down to 0.05 or to 0.1. The ratioω-6/ω-3 fatty acids (C 20 and higher) in the present product ispreferably below 0.3, more preferably below 0.15, e.g. down to 0.03 orto 0.06.

An amount per day as described herein means an amount in a daily dosageunit provided by the composition of the invention. Such a daily dosageunit may be a single dosage, but it may also be divided over two orthree, or even more daily servings. If the composition, as according toa preferred embodiment, is intended for administration as a single unit,the amounts per day as described herein, are preferably the amountspresent in the (preferably packaged) composition unit. Treatmentpreferably involves administration once, twice or three times per day,more preferably once per day for a period of at least 3 weeks.

The present composition preferably comprises 1-40 wt. % DHA based ontotal fatty acids, preferably 3-36 wt. % DHA based on total fatty acids,more preferably 10-30 wt. % DHA based on total fatty acids. The presentcomposition preferably comprises 0.5-20 wt. % EPA based on total fattyacids, preferably 2-10 wt. % EPA based on total fatty acids, morepreferably 5-10wt. % EPA based on total fatty acids. The above-mentionedamounts take into account and optimise several aspects, including taste(e.g. too high LCP levels reduce taste, resulting in a reducedcompliance).

The present composition preferably contains at least one oil selectedfrom fish oil, algae oil and eggs lipids. Preferably the presentcomposition contains fish oil comprising DHA and EPA.

Saturated and Monounsaturated Fatty Acids

The present composition preferably comprises saturated and/ormono-unsaturated fatty acids. The amount of saturated fatty acids ispreferably 6-60 wt. % based on total fatty acids, preferably 12-40 wt.%, more preferably 20-40 wt. % based on total fatty acids. In particularthe amount of C14:0 (myristic acid)+C16:0 (palmitic acid) is preferably5-50 wt. %, preferably 8-36, more preferably 15-30 wt. % wt. % based ontotal fatty acids. The total amount of monounsaturated fatty acids, suchas oleic acid and palmitoleic acid, is preferably between 5 and 40 wt.%, more preferably between 15 and 30 wt. %. A composition with thesepreferred amounts was found to be very effective.

Phospholipids

Preferably, the present composition preferably comprises phospholipids,preferably 0.1-50 wt. % phospholipids based on total weight of lipids,more preferably 0.5-20 wt. %, more preferably between 1 and 10% wt. %,most preferably between 1 and 5 wt. % based on total weight of lipids.The total amount of lipids is preferably between 10 and 30 wt. % on drymatter, and/or between 2 and 10 g lipid per 100 ml for a liquidcomposition. The composition preferably comprises between 0.01 and 1gram lecithin per 100 ml, more preferably between 0.05 and 0.5 gramlecithin per 100 ml. A composition with these preferred amounts wasfound to be very effective.

Choline

Preferably the present composition contains choline and/orphosphatidylcholine. The present method preferably comprises theadministration of more than 50 mg choline per day, preferably 80-2000 mgcholine per day, more preferably 120-1000 mg choline per day, mostpreferably 150-600 mg choline per day. The present compositionpreferably comprises 50 mg to 3 gram choline per 100 ml of the liquidformula, preferably 200 mg-1000 mg choline/100 ml.

Vitamins

The composition may advantageously contain vitamins, preferably vitaminC, vitamin E and B vitamins, more preferably vitamin C, vitamin E,vitamin B6, vitamin B12 and folic acid. Advantageously, vitamin B12 andfolate are included. The present composition preferably comprises50-1000 μg folic acid, more preferably 150-750 μg, most preferably200-500 μg folic acid, per 100 ml liquid product. The present methodpreferably comprises the administration of 50-1000 μg folic acid perday, more preferably 150-750 μg, most preferably 200-500 μg folic acidper day. The present composition preferably comprises 0.5-15 μg vitaminB12, more preferably 1-10 μg, most preferably 1.5-5 μg vitamin B12, per100 ml liquid product. The present method preferably comprises theadministration 0.5-15 μg vitamin B12 per day, more preferably 1-10 μg,most preferably 1.5-5 μg vitamin B12 per day.

Preferably the present composition comprises one or more ofphospholipids, choline, vitamin E, vitamin C, selenium, vitamin B12,vitamin B6 and folic acid, more preferably phospholipids, choline,vitamin E, vitamin C, selenium, vitamin B12, vitamin B6 and folic acid.

Product

The present composition is preferably a ready-to-use liquid, solid, orsemi-liquid product. The present composition is preferably enterallyadministered, more preferably orally. Most preferably the presentcomposition is administered through a straw. When it is a ready-to-useliquid, the daily liquid amount is preferably between 75 and 200 ml perday or per unit, most preferably between 90 and 150 ml/day.

The subjects that can benefit from the method and composition of theinvention often experience problems with eating. Their sensorycapabilities and/or control of muscles can become imparted, as well asin some instances their ambition to apply proper eating habits.Swallowing and/or mastication may be problematic. Hence, the presentcomposition is preferably provided in the form of a drink capable ofbeing ingested through a straw.

The composition according to the invention preferably has a lowviscosity, preferably a viscosity between 1 and 2000 mPa.s measured at ashear rate of 100 sec⁻¹ at 20° C., more preferably a viscosity between 1and 100 mPa.s measured at a shear rate of 100 sec⁻¹ at 20° C. Morepreferably, the present composition is provided in the form of a drinkcapable of being ingested through a straw which makes the product eveneasier to ingest and improves compliance. In a preferred embodiment thepresent composition has a viscosity of 1-80 mPas at a shear rate of 100per sec at 20° C., more preferably of 1-40 mPas at a shear rate of 100per sec at 20° C. These viscosity measurements may for instance beperformed using plate and cone geometry.

To be optimally accepted by the subject, the present compositionpreferably has an osmolality of 300 to 800 mOsm/kg. However, the energydensity of the product is preferably not so high that it interferes withnormal eating habits. When in liquid form, the present productpreferably contains between 0.2 and 3 kcal/ml, more preferably between0.5 and 2, between 0.7 and 1.5 kcal/ml.

Advantageously the present composition contains digestiblecarbohydrates. The present composition preferably contains between 1 and50 gram digestible carbohydrates per 100 ml of a liquid product, morepreferably between 5 and 30 grams per 100 ml, more preferably 10-30grams carbohydrates per 100 ml. The total amount of digestiblecarbohydrates is preferably between 25 and 80 wt. % on dry matter,preferably 40-80 wt. % based on dry matter.

The present composition may further comprise protein, preferably 0.5-10g protein per 100 ml, more preferably 1-6 gram protein per 100 ml, mostpreferably 2-6 gram protein/100 ml. Preferably the present compositioncontain at least 80 wt. % milk derived protein (e.g. whey and/or casein)based on total protein. Proteins enable the manufacturing of palatableproducts, especially for frail elderly.

EXAMPLES Example 1

Packaged composition for the comprising per 125 ml:

Energy 125 kcal; Protein 3.9 g; Carbohydrate 16.5 g; Fat 4.9 g.

Fat includes 1.5 g DHA+EPA, and 106 mg phospholipids (soy lecithin);Choline 400 mg; UMP (uridine monophosphate) 625 mg; Vitamin E 40 mgα-TE; Vitamin C 80 mg; Selenium 60 μg; Vitamin B12 3 μg; Vitamin B6 1mg; Folic acid 400 μg.

Minerals and trace elements: Sodium 125 mg; Potassium 187.5 mg; Chloride156.3 mg; Calcium 100 mg; Phosphorus 87.5 mg; Magnesium 25 mg; Iron 2mg; Zinc 1.5 mg; Copper 225 μg; Manganese 0.41 mg; Molybdenum 12.5 μg;Chromium 8.4 μg; Iodine 16.3 μg. Vitamins: Vit. A 200 μg-RE; vit. D3 0.9μg; vit. K 6.6 μg; Thiamin (B1) 0.19 mg; Riboflavin (B2) 0.2 mg; Niacin(B3) 2.25 mg-NE; Pantothenic acid (B5) 0.66 mg; Biotin 5 μg.

Example 2 Clinical study

Increasing evidence shows a role of nutrients in subjects with impairedmemory function. The present study was done to assess the effect of anintervention with a medical food on memory in drug naïve, very mildAlzheimer's disease (AD) subjects. Drug naïve very mild AD subjects witha MMSE of 24-26 were randomly allocated in a double-blind 12 weeks studyto receive a 125 ml (125 kcal) once-a-day milk-based drink with: (a) theformula according to example 1 (active product) or (b) an iso-caloriccontrol drink according to example 1, but without EPA, DHA,phospholipids, choline, UMP, vitamin E, vitamin C, selenium, vitaminB12, vitamin B6 and folic acid (control product).

Outcome measure was a (delayed) verbal memory task (derived fromWechsler Memory Scale-revised).

Results:

At baseline, there was no significant difference between the grouptreated with the active product and the group treated with the controlproduct. However, there was a significant difference between the twogroups in the change in the delayed verbal memory task (derived fromWechsler Memory scale-revised (WMS-r)) between baseline and after 12weeks of treatment. The group receiving control product (n=66) had anaverage decline of −0.164 with a 95% confidence interval including zero(−0.938 to 0.610) whereas the group receiving active product (n=60) hadan average improvement of 0.983 points on the delayed verbal memoryscale derived from WMS-r with a 95% confidence interval above zero(0.214 to 1.752).

This study demonstrates that intervention with the active product for 12weeks improves memory, particularly delayed recall function in subjectswith MMSE of 24-26 (see table 1).

TABLE 1 Delayed verbal memory score Group Subjects with MMSE 24-26(WMS-r) Control 66 −0.164 Treatment 60 +0.983

1.-7. (canceled)
 8. An enteral composition comprising: a. uridine oruridine phosphate; and b. docosahexaenoic acid and/or eicosapentaenoicacid.
 9. The composition according to claim 8, further comprisingphospholipids, choline, vitamin E, vitamin C, selenium, vitamin B12,vitamin B6 and folic acid.
 10. The composition according to claim 8,comprising 0.1-2 g uridine, calculated as uridine monophosphate, perdaily dosage unit.
 11. The composition according to claim 8, comprising400-5000 mg of the sum of DHA and EPA per daily dosage unit.
 12. Thecomposition according to claim 10, comprising 400-5000 mg of the sum ofDHA and EPA per daily dosage unit.
 13. The composition according toclaim 8, comprising 1-50 gram digestible carbohydrates per 100 ml. 14.The composition according to claim 8, comprising 0.5-10 g protein per100 ml.
 15. The composition according to claim 8, comprising 0.2-3kcal/ml.
 16. The composition according to claim 8, comprising 1-50 gramdigestible carbohydrates per 100 ml, 0.5-10 g protein per 100 ml, and0.2-3 kcal/ml.
 17. The composition according to claim 8, being a liquidproduct, having a viscosity between 1 and 100 mPa.s as measured at ashear rate of 100 s⁻¹ at 20° C.
 18. A method for (i) improving delayedrecall function and/or (ii) the treatment and/or prevention of animpaired delayed recall function of a subject, comprising enterallyadministering to the subject a composition comprising: a. uridine oruridine phosphate; and b. docosahexaenoic acid and/or eicosapentaenoicacid.
 19. The method according to claim 18, wherein the subject has amini-mental state examination of 24-26.
 20. The method according toclaim 18, wherein the composition is enterally administered to thesubject at least one time per day for a period of at least 3 weeks. 21.A method for improving memory and/or treatment or prevention of impairedmemory function in a subject with a mini-mental state examination of 24or 25, comprising enterally administering to the subject a compositioncomprising: a. uridine or uridine phosphate; and b. docosahexaenoic acidand/or eicosapentaenoic acid.
 22. The method according to claim 21,wherein the composition is enterally administered to the subject atleast one time per day for a period of at least 3 weeks.